Insulin-dependent diabetes mellitus (IDDM) is a serious chronic disease resulting from autoimmune destruction of the pancreatic islet cells. Although intense attention has been centered on genetic susceptibility associated with the HLA system on chromosome 6p, other genes also contribute. We propose a coordinated collaborative effort to find all the genes contributing significantly to IDDM susceptibility; four principal investigators will divide the work of systematically screening the human genome with DNA markers (simple tandem repeat polymorphisms, STRPs), and analyzing the results to find markers showing linkage with IDDM. DNA samples from more than 200 families with multiple IDDM siblings will be available from our own labs or purchased from two large repositories. More than 300 STRPs are already available to use as markers, and the number is growing rapidly. Markers spanning the genome at intervals of about 20% recombination will be typed in the first pass through the families; then a second pass will be carried out with additional markers to give a resolution of l0cM. Our own laboratory will screen markers mapping to chromosomes 6, 13-19, 21 and 22; markers on the other autosomes will be the responsibility of PIs of two other grants in this collaboration: Graeme Bell (chromosomes 1-4 and 20), and Patrick Concannon (chromosomes 5 and 7-12). Data from all three labs will be sent to Neil Risch at Yale where analyses will be carried out on the entire collection of markers in a uniform way. When we find linkage to some marker, we will saturate the surrounding region with additional markers, in order to confirm the finding and carry out finer mapping of the gene responsible. If known genes are located in the region of interest, they will be screened for polymorphisms or mutations that might be associated with IDDM. The ultimate goal of this research is to characterize the genetic elements that confer susceptibility, and make possible new interventions and treatments for IDDM.